title: Embryonic stem cells neural differentiation qualifies the role of Wnt/β-Catenin signals in human telencephalic specification and regionalization.
abstract: Wnt-ligands are among key morphogens that mediate patterning of the anterior territories of the developing brain in mammals. We qualified the role of Wnt-signals in regional specification and subregional organization of the human telencephalon using human pluripotent stem cells (hPSCs). One step neural conversion of hPSCs using SMAD inhibitors leads to progenitors with a default rostral identity. It provides an ideal biological substrate for investigating the role of Wnt signaling in both anteroposterior and dorso-ventral processes. Challenging hPSC-neural derivatives with Wnt-antagonists, alone or combined with sonic hedgehog (Shh), we found that Wnt-inhibition promote both telencephalic specification and ventral patterning of telencephalic neural precursors in a dose-dependent manner. Using optimal Wnt-antagonist and Shh-agonist signals we produced human ventral-telencephalic precursors, committed to differentiation into striatal projection neurons both in vitro and in vivo after homotypic transplantation in quinolinate-lesioned rats. This study indicates that sequentially organized Wnt-signals play a key role in the development of human ventral telencephalic territories from which the striatum arise. In addition, the optimized production of hPSC-derived striatal cells described here offers a relevant biological resource for exploring and curing Huntington disease.
authors.affiliation: Inserm U861, I-STEM, AFM, Evry 91030, Cedex, France; UEVE U861, I-STEM, AFM, Evry 91030, Cedex, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Nicoleau
authors.forename: Christine
authors.initials: C
authors.lastname: Varela
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonnefond
authors.forename: Yves
authors.initials: Y
authors.lastname: Maury
authors.forename: Aurore
authors.initials: A
authors.lastname: Bugi
authors.forename: Laetitia
authors.initials: L
authors.lastname: Aubry
authors.forename: Pedro
authors.initials: P
authors.lastname: Viegas
authors.forename: Fany
authors.initials: F
authors.lastname: Bourgois-Rocha
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.forename: Anselme L
authors.initials: AL
authors.lastname: Perrier
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000628:therapy; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D013687:Telencephalon / Q000166:cytology*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D053823:Hedgehog Proteins; D006575:Heterocyclic Compounds, 3-Ring; C509239:SHH protein, human; C544261:XAV939
keywords: Cell therapy; Developmental biology; Forebrain specification; Huntington disease; Neural differentiation; Pluripotent stem cells; Striatum